Steroid sulphatase inhibitors

• US 6,903,084 B2
• Filed: 02/27/2001
• Issued: 06/07/2005
• Est. Priority Date: 08/29/1991
• Status: Expired due to Fees

• Current Assignee: Sterix Limited (Ipsen Sa)
• Original Assignee: Sterix Limited (Ipsen Sa)
• Inventors: Reed, Michael John, Potter, Barry Victor Lloyd
• Primary Examiner(s): Badio, Barbara P.
• Application Number:
  US09/794,853
• Publication Number:
  US 20010018435A1
• Time in Patent Office: 1,561 Days
• Field of Search: 552/626, 574/178
• US Class Current: 514/178
• CPC Class Codes: A61K 31/37 Coumarins, e.g. psoralen
• CPC Class Codes: C07D 311/16 substituted in position 7
• CPC Class Codes: C07D 311/30 not hydrogenated in the hetero ring, e.g. flavones
• CPC Class Codes: C07D 311/32 2,3-Dihydro derivatives, e.g. flavanones
• CPC Class Codes: C07D 311/36 not hydrogenated in the hetero ring, e.g. isoflavones
• CPC Class Codes: C07J 41/0072 the A ring of the steroid being aromatic

Abstract

A method of inhibiting steroid sulphatase activity in a subject in need of same is described.

The method comprises administering to said subject a steroid sulphatase inhibiting amount of a ring system compound; which ring system compound comprises a ring to which is attached a sulphamate group of the formula
wherein each of R₁ and R₂ is independently selected from H, alkyl, alkenyl, cycloalkyl and aryl, or together represent allylene optionally containing one or more hetero atoms or groups in the alkylene chain; and wherein said compound is an inhibitor of an enzyme having steroid sulphatase activity (E.C.3.1.6.2); and if the sulphamate group of said compound is replaced with a sulphate group to form a sulphate compound and incubated with a steroid sulphatase enzyme (E.C.3.1.6.2) at a pH 7.4 and 37° C. it would provide a K_m value of less than 50 μM.

Claims

1. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a pharmaceutically effective amount of a compound of the formula (II)

wherein R₁ and R₂ are independently H or C₁-C₅ alkyl, and at least one of R₁ and R₂ is H;

and the ring system ABCD represents a steroid nucleus, selected from the group consisting of dehydroepiandrosterone, oestrone, 2-OH-oestrone, 7α

-OH-oestrone, 2-methoxy-oestrone, 16α

-OH-oestrone, 4-OH-oestrone, 16β

-OH-oestrone, 6α

-OH-oestrone, 2-OH-17β

-oestradiol, 6α

-OH-17β

-oestradiol, 16β

-OH-7α

-oestradiol, 17β

-oestradiol, 2-methoxy-17β

-oestradiol, 7α

-OH-17β

-oestradiol, 16α

-OH-17α

-oestradiol, 17α

-ethinyl-17β

-oestradiol, 4-OH-17β

-oestradiol, 16α

-OH-17α

-oestradiol, 17α

-oestradiol, oestradiol, 4-OH-oestradiol, 2-OH-oestradiol, 6α

-OH-oestradiol, 2-methoxy-oestradiol, 7α

-OH-oestradiol, 6α

-OH-dehydroepiandrosterone, 16α

-OH-dehydroepiandrosterone, 7α

-OH-dehydroepiandrosterone, and 16β

-OH-dehydroepiandrosterone, wherein said compound is an inhibitor of an enzyme having steroid sulphatase activity (EC 3.1.6.2); and

wherein when the sulphamic acid ester group of said compound is replaced with a sulphate group to form a sulphate compound and incubated with a steroid sulphatase enzyme (EC 3.1.6.2) at a pH 7.4 and 37°

C. it provides a K_m value of less than 50 μ

M, or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition of claim 1 wherein the steroid nucleus has the ring system ABCD of oestrone.

3. The pharmaceutical composition of claim 1 wherein the steroid nucleus has the ring system ABCD of 17β

-oestradiol.

4. The pharmaceutical composition of claim 1 wherein the steroid nucleus has the ring system ABCD of 17α

-ethinyl-17β

-oestradiol.

5. The pharmaceutical composition of claim 1 wherein the steroid nucleus has the ring system ABCD of 17α

-oestradiol.

6. The pharmaceutical composition of claim 1 wherein the steroid nucleus has the ring system ABCD of oestradiol.

7. The pharmaceutical composition of claim 1 wherein R₁ and R₂ are H.

8. The pharmaceutical composition of claim 2 wherein R₁ and R₂ are H.

9. The pharmaceutical composition of claim 3 wherein R₁ and R₂ are H.

10. The pharmaceutical composition of claim 4 wherein R₁ and R₂ are H.

11. The pharmaceutical composition of claim 5 wherein R₁ and R₂ are H.

12. The pharmaceutical composition of claim 6 wherein R₁ and R₂ are H.

13. A purified compound of the formula (II)

wherein R₁ and R₂ are independently H or C₁-C₅ alkyl, and at least one of R₁ and R₂ is H;

and the ring system ABCD represents a steroid nucleus, selected from the group consisting of dehydroepiandrosterone, oestrone, 2-OH-oestrone, 7α

-OH-oestrone, 2-methoxy-oestrone, 16α

-OH-oestrone, 4-OH-oestrone, 16β

-OH-oestrone, 6α

-OH-oestrone, 2-OH-17β

-oestradiol, 6α

-OH-17β

-oestradiol, 16β

-OH-7α

-oestradiol, 17β

-oestradiol, 2-methoxy-17β

-oestradiol, 7α

-OH-17β

-oestradiol, 16α

-OH-17β

-oestradiol, 17α

-ethinyl-17β

-oestradiol, 4-OH-17β

-oestradiol, 16α

-OH-17α

-oestradiol, 17α

-oestradiol, oestradiol, 4-OH-oestradiol, 2-OH-oestradiol, 6α

-OH-oestradiol, 2-methoxy-oestradiol, 7α

-OH-oestradiol, 6α

-OH-dehydroepiandrosterone, 16α

-OH-dehydroepiandrosterone, 7α

-OH-dehydroepiandrosterone, and 16β

-OH-dehydroepiandrosterone, wherein said compound is an inhibitor of an enzyme having steroid sulphatase activity (EC 3.1.6.2); and

wherein when the sulphamic acid ester group of said compound is replaced with a sulphate group to form a sulphate compound and incubated with a steroid sulphatase enzyme (EC 3.1.6.2) at a pH 7.4 and 37°

C. it provides a K_m value of less than 50 μ

M, or a pharmaceutically acceptable salt thereof.

14. The purified compound of claim 13 wherein the steroid nucleus has the ring system ABCD of oestrone.

15. The purified compound of claim 13 wherein the steroid nucleus has the ring system ABCD of 17β

-oestradiol.

16. The purified compound of claim 13 wherein the steroid nucleus has the ring system ABCD of 17α

-ethinyl-17β

-oestradiol.

17. The purified compound of claim 13 wherein the steroid nucleus has the ring system ABCD of 17α

-oestradiol.

18. The purified compound of claim 13 wherein the steroid nucleus has the ring system ABCD of oestradiol.

19. The purified compound of claim 13 wherein R₁ and R₂ are H.

20. The purified compound of claim 14 wherein R₁ and R₂ are H.

21. The purified compound of claim 15 wherein R₁ and R₂ are H.

22. The purified compound of claim 16 wherein R₁ and R₂ are H.

23. The purified compound of claim 17 wherein R₁ and R₂ are H.

24. The purified compound of claim 18 wherein R₁ and R₂ are H.

31. The pharmaceutical composition of claim 24 wherein at least one of R₁ and R₂ is H.

25. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a pharmaceutically effective amount or a compound of the formula (II)

wherein R₁ and R₂ are independently H or C₁-C₅ alkyl;

and

the ring system ABCD represents a steroid nucleus, selected from the group consisting of dehydroepiandrosterone, 2-OH-oestrone, 7α

-OH-oestrone, 2-methoxy-oestrone, 16α

-OH-oestrone, 4-OH-oestrone, 16β

-OH-oestrone, 6α

-OH-oestrone, 2-OH-17β

-oestradiol, 6α

-OH-17β

-oestradiol, 16β

-OH-7α

-oestradiol, 17β

-oestradiol, 2-methoxy-17β

-oestradiol, 7α

-OH-17β

-oestradiol, 16α

-OH-17β

-oestradiol, 4-OH-17β

-oestradiol, 16α

-OH-17α

-oestradiol, 17α

-oestradiol, oestradiol, 4-OH-oestradiol, 2-OH-oestradiol, 6α

-OH-oestradiol, 2-methoxy-oestradiol, 7α

-OH-oe 6α

-OH-dehydroepiandrosterone, 16α

-OH-dehydroepiandrosterone, 7α

-OH-dehydroepiandrosterone, and 16β

-dehydroepiandrosterone.

wherein said compound is an inhibitor of an enzyme having steroid sulphatase activity (EC 3.1.6.2); and

wherein when the sulphamic acid ester group of said compound is replaced with a sulphate group to form a sulphate compound and incubated with a steroid sulphatase enzyme (EC 3.1.6.2) at a pH 7.4 and 37°

C. it provides a K_m value of less than 50 μ

M, or a pharmaceutically acceptable salt thereof.

26. The pharmaceutical composition of claim 25 wherein the steroid nucleus has the ring ABCD of 17β

-oestradiol.

27. The pharmaceutical composition of claim 25 wherein the steroid nucleus has the ring ABCD of 17α

-oestradiol.

28. The pharmaceutical composition of claim 25 wherein the steroid nucleus has the ring system ABCD of oestradiol.

29. The pharmaceutical composition of claim 25 wherein at least one of R₁ and R₂ is H.

30. The pharmaceutical composition of claim 26 wherein at least one of R₁ and R₂ is H.

32. The pharmaceutical composition of claim 28 wherein at least one of R₁ and R₂ is H.

33. The pharmaceutical composition of claim 25 wherein R₁ and R₂ are H.

34. The pharmaceutical composition of claim 26 wherein R₁ and R₂ are H.

35. The pharmaceutical composition of claim 27 wherein R₁ and R₂ are H.

36. The pharmaceutical composition of claim 28 wherein R₁ and R₂ are H.

37. A purified compound of the formula (II)

wherein R₁ and R₂ are independently H or C₁-C₅ alkyl;

and

the ring system ABCD represents a steroid nucleus, selected from the group consisting of dehydroepiandrosterone, 2-OH-oestrone, 7α

-OH-oestrone, 2-methoxy-oestrone, 16α

-OH-oestrone, 4-OH-oestrone, 16β

-OH-oestrone, 6α

-OH-oestrone, 2-OH-17β

-oestradiol, 6α

-OH-17β

-oestradiol, 16β

-OH-7α

-oestradiol, 17β

-oestradiol, 2-methoxy-17β

-oestradiol, 7α

-OH-17β

-oestradiol, 16α

-OH-17β

-oestradiol, 4-OH-17β

-oestradiol, 16α

-OH-17α

-oestradiol, 17α

-oestradiol, oestradiol, 4-OH-oestradiol, 2-OH-oestradiol, 6α

-OH-oestradiol, 2-methoxy-oestradiol, 17α

-OH-o 6α

-OH-dehydroepiandrosterone, 16α

-OH-dehydroepiandrosterone, 7α

-OH-dehydroepiandrosterone, and 16β

-OH-dehydroepiandrosterone.

wherein said compound is an inhibitor of an enzyme having steroid sulphatase activity (EC 3.1.6.2); and

wherein when the sulphamic acid ester group of said compound is replaced with a sulphate group to form a sulphate compound and incubated with a steroid sulphatase enzyme (EC 3.1.6.2) at a pH 7.4 and 37°

C. it provides a K_m value of less than 50 μ

M, or a pharmaceutically acceptable salt thereof.

38. The purified compound or claim 37 wherein the steroid nucleus has the ring system ABCD of 17β

-oestradiol.

39. The purified compound of claim 37 wherein the steroid nucleus has the ring system ABCD of 17α

-oestradiol.

40. The purified compound of claim 37 wherein the steroid nucleus has the ring system ABCD of oestradiol.

41. The purified compound of claim 37 wherein at least one of R₁ and R₂ is H.

42. The purified compound of claim 38 wherein at least one of R₁ and R₂ is H.

43. The purified compound of claim 39 wherein at least one of R₁ and R₂ is H.

44. The purified compound of claim 40 wherein at least one of R₁ and R₂ is H.

45. The purified compound of claim 37 wherein R₁ and R₂ are H.

46. The purified compound of claim 38 wherein R₁ and R₂ are H.

47. The purified compound of claim 39 wherein R₁ and R₂ are H.

48. The purified compound of claim 40 wherein R₁ and R₂ are H.